Salvage radiotherapy for locally recurrent cervical and endometrial carcinoma: clinical outcomes and toxicities

Background The management of locally recurrent gynecological carcinoma remains a challenge due to the limited availability of data. This study aims to share our institutional experience in using definitive radiotherapy (RT) for the treatment of locally recurrent cervical and endometrial carcinoma. Methods The study retrospectively reviewed 20 patients in our hospital completing salvage 3D image-based HDR brachytherapy, with or without EBRT, for locally recurrent cervical and endometrial carcinoma after surgery. The Kaplan–Meier method was applied to estimate the disease-free survival (DFS) and overall survival (OS). The toxicities were assessed by CTCAEv5. Results During a median observation period of 21 months, the study reported a tumor objective response rate of 95%. The 3-year DFS and OS rates were 89.4% and 90.9%, respectively. The EBRT combined with brachytherapy achieved a median cumulative dose of 88 Gy to CTV D90. 14 patients received concurrent and/or systemic chemotherapy. Two patients suffered locoregional recurrence after salvage treatment, one of whom only received salvage brachytherapy for prior RT history. The analysis identified significant predictors for DFS, including tumor histology and FIGO stage. 5 patients observed acute grade 1–2 rectal (15%) or genitourinary (10%) toxicities. Late toxicities including grade 1–2 rectal bleeding (10%) and grade 2 pelvic fracture (5%) were seen in 3 patients. Conclusions 3D image-guided brachytherapy combined with EBRT shows effective tumor control and acceptable toxicity profile for women with locally recurrent gynecologic cancer. The success in managing vaginal recurrence is notably influenced by histologic subtype and FIGO staging.


Introduction
Cervical cancer and endometrial cancer are the two main tumor types in gynecological oncology, with a long-term high incidence and mortality [1].In many low-income and middle-income countries, cervical cancer shows slowly reduced or even increased incidence and mortality, which results in heavy health and economic burden [2,3].Meanwhile, endometrial cancer demonstrates a continued rise in incidence worldwide and has the fastest increasing morbidity in women [1,4].For patients with early-stage disease, radical surgery is recommended, and subsequent adjuvant treatment is determined according to the pathology.While there are still approximately 5-10% of patients suffered postoperative locoregional recurrence [5][6][7][8].Considering the feasibility of surgical resection, definitive radiotherapy (RT) involving external beam radiotherapy (EBRT) and brachytherapy is more widely used for locally recurrent patients without previous RT history.After treatment for relapse, long-term disease-free survival rates of approximately 40-70% have been reported in some situations [9][10][11].
Recently, advances in radiotherapy have achieved superior dosimetric outcomes and reduced toxicity.Application of 3D image-guided brachytherapy, especially interstitial brachytherapy, facilitates a higher dose to the clinical target volume (CTV) while minimizing the dose to adjacent organs at risk (OARs) [12,13].Herein, we retrospectively reviewed the clinical outcomes and toxicities of twenty patients with postoperative localized recurrence of gynecological tumors after undergoing 3D image-based high-dose-rate (HDR) brachytherapy with (or without) EBRT and chemotherapy.We also evaluated the prognostic factors associated with outcomes after salvage therapy to help understand the disease development and make individualized therapies.

Study design
All patients treated in our hospital from October 2020 to September 2023 for locally recurrent cervical or endometrial cancer after surgery were retrospectively reviewed.The inclusion criteria include: (1) pathologically confirmed vaginal recurrence with no evidence of distant metastasis; (2) finishing HDR-brachytherapy delivered in at least four fractions, with or without external beam radiotherapy.This study was approved by the institutional ethics committee of Shanghai Sixth People's Hospital.

Treatment modalities for recurrence
For patients without prior pelvic radiation, definitive RT consisted of EBRT with intensity-modulated radiation therapy (IMRT) and 3D image-based HDR brachytherapy was applied.If the patients have completed postoperative pelvic EBRT before, only brachytherapy was applied.Moreover, concurrent cisplatin (40mg/m 2 , weekly) and/ or systemic therapy involving platinum and paclitaxel chemotherapy were also performed based on the physical status of patients during treatment.EBRT was up to a dose of 45-50.4Gy to the entire vagina plus pelvic lymph nodes at 1.8 Gy per fraction in 25-28 fractions.The CTV for EBRT encompasses the gross tumor, entire vagina, and pelvic lymph nodes including the common iliac, external iliac, internal iliac, obturator, and presacral nodal.Inguinal lymph nodes were also involved for distal vaginal lesions.As to the patients with vaginal plus lymph node recurrence, IMRT delivered a simultaneous integrated boost to 61.6 Gy at 2.2 Gy per fraction to the involved lymph nodes.After EBRT, the patients received image-based HDR brachytherapy at a dose of 24-35 Gy to the vaginal recurrence at 4-6 Gy per fraction in 4-6 fractions.Intracavity brachytherapy by ovoids or cylinder and/or interstitial brachytherapy by free-hand needles was chosen according to patients and tumor anatomy, referring to the extent of disease on pretreatment CT or MRI imaging.All brachytherapy fractions were individually optimized to the CTV with 3-dimensional CT-based planning.The high-risk CTV for brachytherapy involves the residual tumor and entire vaginal surface.Radiation was delivered using an after-loaded 192Ir source in two fractions per week.

Follow-up and statistical analysis
Outcome measures of disease status included diseasefree survival (DFS) and overall survival (OS).DFS was defined as the time from the start of the salvage radiation therapy to the last follow-up attendance or any disease recurrence.OS was defined as the time from the start of salvage radiation therapy to the last follow-up attendance or death from any cause.Besides, we assessed and recorded the treatment-related toxicities by Common Terminology Criteria for Adverse Events version 5 (CTCAEv5).Cumulative DFS and OS were calculated by the Kaplan-Meier method.Univariate survival curve comparisons were performed by the log-rank test to identify prognostic factors for outcomes.All statistical analyses were carried out with GraphPad v9.4.0.

Patients and treatment characteristics
A total of twenty patients were reviewed and analyzed.The median age of patients undergoing initial surgery was 55 years (range 32-75).Cervical cancer was the predominant cancer type (n = 17).According to the surgical histology, most lesions were precancerous or early-stage cancer (FIGO I).One patient received postoperative pelvic EBRT at a dose of 50.4 Gy in 28 fractions and concurrent nedaplatin at 40 mg weekly for 5 cycles as adjuvant treatment.Besides, three patients accepted adjuvant platinum and paclitaxel chemotherapy alone for 2-3 cycles after surgery.More characteristics of patients and initial therapy are presented in Table 1.
The median time from primary hysterectomy to vaginal recurrence was 40.5 months (range 10.0-117.0)(Fig. 1).80% of recurrences (n = 16) were limited to the vagina, the rest (n = 4) involved both vagina and pelvic or inguinal lymph nodes.Except for one patient who only received salvage brachytherapy because of previous RT history, all other patients (n = 19) received definitive RT involving pelvic EBRT and 3D image-guided HDR vaginal brachytherapy.Based on patient anatomy and the residual tumor size and extension, 55% of patients (n = 11) had intracavity brachytherapy, 35% of patients (n = 7) had interstitial brachytherapy, and the rest (n = 2) had hybrid brachytherapy including both.The salvage radiation treatment achieved a median dose of 88 Gy to 90% clinical target volume (D90) in the equivalent dose in 2 Gy fractions (EQD2).The cumulative dose of CTV D90 was above 75 Gy in all patients except one only receiving brachytherapy.Along with radiotherapy, concurrent cisplatin and/or systemic therapy was performed in 70% of patients (n = 14).The other details of the salvage treatment are listed in Table 2.

Clinical outcomes and prognostic factors
After salvage treatment, the objective response rate was 95%.With a median follow-up time of 21 months (range: 3-38), the 3-year DFS and OS were 89.4% and 90.9%, respectively (Fig. 2A-B).Two patients (10%) had locoregional recurrence at 6 and 8 months after salvage treatment, and one of them only received salvage brachytherapy because of prior pelvic RT history.No distant failure was found during the follow-up.
On univariate analysis for disease control, histology of cervical cancer, FIGO stage after initial surgery were significantly prognostic for DFS (Table 3, all p ≤ 0.005).Patients with cervical adenocarcinoma (ADC), higher FIGO stage showed worse outcomes after salvage therapy (Fig. 3A-B).Meanwhile, age at recurrence, the interval between initial surgery and recurrence, tumor grade, pelvic nodal recurrence, brachytherapy type, and chemotherapy use had no predictive value for DFS (Table 3, all p > 0.1).
In the present study, with a median dose delivery of 88 Gy prescribed to CTV, no patients suffered grade 3 or higher toxicities.The median D2cc for the bladder, rectum, and bowel were 64.6 Gy, 62.4 Gy and 52.2 Gy, respectively.According to the dose constraint recommended by ASTRO clinical practice guideline [23], ideal dose constraints for the bladder, rectum, and bowel were achieved in 100%, 60%, and 95% of the patients in the study.No one had the dose of OARs exceeded the maximum dose constraints.Limitations of this study included its retrospective nature and small sample size, which resulted in the preclusion of multivariate analysis.Nevertheless, our data contributed to the limited number of related series in the literature, as well as shared our institutional experience in exploring treatment modalities and dose prescriptions for treating isolated vaginal recurrence.

Conclusion
In conclusion, our study indicates that image-guided brachytherapy combined with EBRT could achieve favorable tumor control and tolerable treatment-related toxicities in patients with locoregionally recurrent gynecological cancer.Tumor histology and FIGO stage revealed prognostic value for clinical outcomes.

Fig. 1
Fig. 1 Initial recurrence-free survival of patients in the study

Fig. 2
Fig. 2 Kaplan-Meier estimates of (A) DFS and (B) OS for patients with vaginal recurrence after salvage therapy

Table 1
Initial clinical and treatment characteristics Abbreviation CC: Cervical cancer; SCC: Squamous cell carcinoma; ADC: Adenocarcinoma; DFS: Disease free survival

Table 2
Recurrence characteristics and salvage therapy parameters

Table 3
Prognostic factors for PFS following salvage therapy for the vaginal recurrence